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TBI chronically alters neuronal function. Living Tuj1 + Thy1 + neuronal counts in the ipsilateral hemisphere of sham and chronic TBI mice were estimated using counting beads (Student's unpaired t-test; A). Representative dot plots illustrate intracellular staining for synaptophysin in neurons (B). The frequency of synaptophysin-positive neurons was quantified (C). Representative dot plots depict intracellular staining for PSD-95 in sham and chronic TBI neurons (D). The frequency of PSD-95-positive neurons was quantified (E). Autophagic vesicles were measured using Cyto-ID dye. Representative dot plots show the percentage of autophagosome-positive neurons in sham and TBI groups (F). Quantification of autophagosome-positive neurons is shown (G). Oxidative stress was measured using DHR123 and the relative level of reactive oxygen species production by the Tuj1 + Thy1 + neuronal population is shown in the representative histogram (H). MFI quantification of DHR123-positive neurons is shown (I). Mitochondrial membrane potential was measured using MitoSpy Red CMXRos and the relative level of mitochondrial function in neurons is depicted in the representative histogram (J). MFI quantification of MitoSpy Red-positive neurons is shown (K). Mitochondrial mass was measured using MitoSpy Green FM and the relative level of mitochondrial content in neurons is depicted in the representative histogram (L). MFI quantification of MitoSpy Green-positive neurons is shown (M). For all experiments, N = 5/group. Error bars show mean SEM. Abbreviation: FMO fluorescence minus one control, MFI mean fluorescence intensity, DHR123 dihydrorhodamine 123, Max maximum, SSC-A side scatter-area, TBI traumatic brain injury, SEM standard error of mean. *p < .05.
Source publication
Traumatic brain injury (TBI) can cause progressive neurodegeneration, sustained neuroinflammation and chronic neurological dysfunction. Few experimental studies have explored the long-term neurobehavioral and functional cellular changes beyond several months. The present study examined the effects of a single moderate-level TBI on functional outcom...
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... begin our analysis of the Thy1 + Tuj1 + neuronal population, we performed an estimated cell count using absolute counting beads. The ipsilateral hemisphere of chronic CCI mice had significantly fewer neurons than sham controls, consistent with previous studies (N = 5/ group, p ≤ .05, Fig. 5A). The number and percentage of synaptophysinand PSD-95-positive neurons were also significantly decreased after TBI, implying injury-induced diminishment in synaptic plasticity (p ≤ .05, Fig. 5B-E). Neurons isolated from TBI mice showed increased expression of DHR123 relative to sham, indicating higher oxidative stress levels (p ≤ .05, ...
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... ipsilateral hemisphere of chronic CCI mice had significantly fewer neurons than sham controls, consistent with previous studies (N = 5/ group, p ≤ .05, Fig. 5A). The number and percentage of synaptophysinand PSD-95-positive neurons were also significantly decreased after TBI, implying injury-induced diminishment in synaptic plasticity (p ≤ .05, Fig. 5B-E). Neurons isolated from TBI mice showed increased expression of DHR123 relative to sham, indicating higher oxidative stress levels (p ≤ .05, Fig. 5H-I). To examine other aspects of neuronal health we measured mitochondrial function using cell-permeant fluorogenic chemical reagents. Consistent with our viability staining, all living ...
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... Fig. 5A). The number and percentage of synaptophysinand PSD-95-positive neurons were also significantly decreased after TBI, implying injury-induced diminishment in synaptic plasticity (p ≤ .05, Fig. 5B-E). Neurons isolated from TBI mice showed increased expression of DHR123 relative to sham, indicating higher oxidative stress levels (p ≤ .05, Fig. 5H-I). To examine other aspects of neuronal health we measured mitochondrial function using cell-permeant fluorogenic chemical reagents. Consistent with our viability staining, all living neurons had functional mitochondria, however, fluorescent intensities were greater in neurons from injured mice (p ≤ .05, Fig. 5J-K). To determine if ...
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... oxidative stress levels (p ≤ .05, Fig. 5H-I). To examine other aspects of neuronal health we measured mitochondrial function using cell-permeant fluorogenic chemical reagents. Consistent with our viability staining, all living neurons had functional mitochondria, however, fluorescent intensities were greater in neurons from injured mice (p ≤ .05, Fig. 5J-K). To determine if increased mitochondrial activity was due to higher mitochondrial content we labeled cells with MitoSpy Green probe. Indeed, neurons from injured mice had greater mitochondrial mass than sham controls (p ≤ .05, Fig. 5L-M). Lastly, to further highlight the utility of this approach to measuring neuronal function, we ...
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... functional mitochondria, however, fluorescent intensities were greater in neurons from injured mice (p ≤ .05, Fig. 5J-K). To determine if increased mitochondrial activity was due to higher mitochondrial content we labeled cells with MitoSpy Green probe. Indeed, neurons from injured mice had greater mitochondrial mass than sham controls (p ≤ .05, Fig. 5L-M). Lastly, to further highlight the utility of this approach to measuring neuronal function, we examined autophagic activity. Neurons from chronically injured mice showed higher frequencies LC3-positive autophagosome formation compared to sham mice, consistent with previous findings for acute time points (p ≤ .05, Fig. 5F-G) (Sarkar et ...
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... sham controls (p ≤ .05, Fig. 5L-M). Lastly, to further highlight the utility of this approach to measuring neuronal function, we examined autophagic activity. Neurons from chronically injured mice showed higher frequencies LC3-positive autophagosome formation compared to sham mice, consistent with previous findings for acute time points (p ≤ .05, Fig. 5F-G) (Sarkar et al., 2014). These findings support the use Fig. 4. Gating strategy for identifying neuronal populations in the brain using flow cytometry. Representative dot plots show the identification of living, nucleated cells in single cell suspensions of brain tissue, based on Zombie Aqua and Draq5 staining pattern (A). Using a ...
Citations
... Since the current CCI model causes significant tissue loss in the motor and sensory cortices, mice from the CCI-Veh group exhibited, as expected, a significant decrease in percent nestlet usage and nesting score compared to that of the Sham-Veh group. This result is consistent with a previous study using a similar chronic CCI mouse model (Ritzel et al., 2020). On the other hand, mice from CCI-Nic and CCI-Nic Withdrawal groups displayed F I G U R E 5 Chronic nicotine exposure increases mBDNF expression and up-regulates neuronal BDNF-TrkB signalling in the ipsilateral cortex. ...
... Individuals with severe TBI suffer from long-lasting sensorimotor deficits due to significant neuronal loss, diffuse axonal injuries and chronic neuroinflammation. While studies using moderate and diffuse TBI rodent models showed that nesting behaviour could recover to baseline level at 7 days post CCI (Muccigrosso et al., 2016), severe TBI models presented persistent nesting deficits that last for months (Ritzel et al., 2020). In this current study, both the CCI-Nic and the CCI-Nic Withdrawal groups showed significantly enhanced function recovery, suggesting that the functional improvement is not dependent on nicotine's transient modulating effects on dopamine (DA)mediated motivation change but a true improvement in long-term functional recovery after CCI. ...
Background and Purpose
Traumatic brain injury (TBI) causes lifelong physical and psychological dysfunction in affected individuals. The current study investigated the effects of chronic nicotine exposure via E‐cigarettes (E‐cig) (vaping) on TBI‐associated behavioural and biochemical changes.
Experimental Approach
Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E‐cig vapour for 6 weeks. Sensorimotor functions, locomotion, and sociability were subsequently evaluated by nesting, open field, and social approach tests, respectively. Immunoblots were conducted to examine the expression of mature brain‐derived neurotrophic factor (mBDNF) and associated downstream proteins (p‐Erk, p‐Akt). Histological analyses were performed to evaluate neuronal survival and neuroinflammation.
Key Results
Post‐injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histological analysis revealed increased survival of cortical neurons in the perilesion cortex with chronic nicotine exposure. Immunoblots revealed that chronic nicotine exposure significantly up‐regulated mBDNF, p‐Erk and p‐Akt expression in the perilesion cortex of CCI mice. Immunofluorescence microscopy indicated that elevated mBDNF and p‐Akt expression were mainly localized within cortical neurons. Immunolabelling of Iba1 demonstrated that chronic nicotine exposure attenuated microglia‐mediated neuroinflammation.
Conclusions and Implications
Post‐injury chronic nicotine exposure via vaping facilitates recovery of sensorimotor function by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signalling. These findings suggest potential neuroprotective properties of nicotine despite its highly addictive nature. Thus, understanding the multifaceted effects of chronic nicotine exposure on TBI‐associated symptoms is crucial for paving the way for informed and properly managed therapeutic interventions.
... Indeed, our lab and others have experimentally shown that peripheral infections during acute and chronic stages of TBI are more severe compared to sham controls and often cause bidirectional damage [21][22][23][24][25][26]. Although we have demonstrated that chronic microglial activation can aggravate post-traumatic neurodegeneration [27][28][29][30], the long-term consequences and progression of bone marrow dysfunction following brain injury remains largely undocumented. ...
... Recently we reported that moderate-to-severe TBI caused alterations in the bone marrow compartment that subsequently led to leukopenia and reduction in white blood cell production in the femur [28,44]. To begin our next series of investigations into the brain-bone marrow axis, we examined the effect of TBI on stress-induced myelopoiesis. ...
... Acute stress-induce myelopoiesis was accompanied by neutrophilia and peripheral immune suppression during the early phase. Deficits in phagocytosis and elevated oxidative stress levels persisted for months after injury, associated with the development of leukopenia and bone marrow failure at one-year post-injury [28,53]. Importantly, we found that bone marrow-derived macrophage cultures harvested from chronic (90d) TBI mice exhibited significantly higher sensitivity to LPS stimulation Fig. 9 The senolytic drug, ABT-263, has beneficial effects on normal age-related motor function but does not confer robust protection to acute TBI. ...
Background
It is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined.
Methods
To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) hosts. Immune changes were evaluated by flow cytometry, multiplex ELISA, and NanoString technology. Moderate-to-severe TBI was induced by controlled cortical impact injury and neurological function was measured using a battery of behavioral tests.
Results
TBI induced chronic alterations in the transcriptome of BM lineage⁻c-Kit⁺Sca1⁺ (LSK+) cells in C57BL/6 mice, including modified epigenetic and senescence pathways. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI at 8 weeks and 8 months post-reconstitution showed that longer reconstitution periods (i.e., time post-injury) were associated with increased microgliosis and leukocyte infiltration. Pre-treatment with a senolytic agent, ABT-263, significantly improved behavioral performance of aged C57BL/6 mice at baseline, although it did not attenuate neuroinflammation in the acutely injured brain.
Conclusions
TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in hematopoiesis, innate immunity, and neurological function, as well as altered sensitivity to subsequent brain injury.
... Similarly, preclinical studies have indicated that swift microglial reactivity is observed within minutes in animal models of both mild and severe traumatic brain injury (94). This process can persist for days, weeks, and even months after experimental traumatic brain injury, varying based on the types of lesions involved (95). Remarkably, an analysis of the temporal dynamics of microglia polarization following traumatic brain injury revealed the activation of both M1-like and M2-like polarized microglia during the initial stages after the injury (96). ...
Macrophage/microglia function as immune defense and homeostatic cells that originate from bone marrow progenitor cells. Macrophage/microglia activation is historically divided into proinflammatory M1 or anti-inflammatory M2 states based on intracellular dynamics and protein production. The polarization of macrophages/microglia involves a pivotal impact in modulating the development of inflammatory disorders, namely lung and traumatic brain injuries. Recent evidence indicates shared signaling pathways in lung and traumatic brain injuries, regulated through non-coding RNAs (ncRNAs) loaded into extracellular vesicles (EVs). This packaging protects ncRNAs from degradation. These vesicles are subcellular components released through a paracellular mechanism, constituting a group of nanoparticles that involve exosomes, microvesicles, and apoptotic bodies. EVs are characterized by a double-layered membrane and are abound with proteins, nucleic acids, and other bioactive compounds. ncRNAs are RNA molecules with functional roles, despite their absence of coding capacity. They actively participate in the regulation of mRNA expression and function through various mechanisms. Recent studies pointed out that selective packaging of ncRNAs into EVs plays a role in modulating distinct facets of macrophage/microglia polarization, under conditions of lung and traumatic brain injuries. This study will explore the latest findings regarding the role of EVs in the progression of lung and traumatic brain injuries, with a specific focus on the involvement of ncRNAs within these vesicles. The conclusion of this review will emphasize the clinical opportunities presented by EV-ncRNAs, underscoring their potential functions as both biomarkers and targets for therapeutic interventions.
... Social interactions are impaired after TBI with reductions in interpersonal communication, 9 time with friends and families, 10,11 and is evident in children 12,13 and adults. 14,15 Social behavior is also diminished in adult mice after a single 16,17 or repeated-mild TBI, 18,19 and in pediatric models of TBI. 20 Social isolation in rodents reflects increased neuropathology after TBI, 21 however, increased social interaction post-injury is known to facilitate recovery. ...
Traumatic brain injury (TBI) survivors face debilitating long-term psychosocial consequences, including social isolation and depression. Acute TBI modifies neurovascular physiology and behavior but a gap in our understanding are the chronic physiological implications of altered brain perfusion on behavioral activities, particularly social interactions.
We investigated longitudinal functional vascular networks across the brain for 2-months post- TBI and its impact on social behavior. Adult C57/BL6 male mice received a moderate cortical TBI. Behavior (foot-fault, open-field, 3-chamber social preference) was assessed at baseline, 3-, 7-, 14-, 30-, and 60-days post injury (dpi) followed by magnetic resonance imaging (MRI, 9.4T). Anatomical MRI (T2-weighted), dynamic susceptibility contrast (DSC) perfusion weighted MRI (PWI) were acquired at each temporal epoch. After the final 60dpi MRI, animals underwent transcardial perfusion fixation to map angioarchitecture. MRI data were analyzed using standardized protocols followed by cross-correlations between social behavior, cerebral perfusion, and vascular metrics.
Social behavior deficits at 60dpi emerged as reduced interaction with a familiar cage-mate (partner). We observed multiphasic decrements in cerebral blood flow (CBF) encompassing lesion and perilesional cortex where acute reductions at 3-14dpi partially recovered by 30dpi, followed by significant reductions in perfusion at 60dpi. The CBF perturbations extended antero-posteriorly from the ipsilateral TBI impact site but also adulterated contralateral brain regions. CBF reductions impacted regions known to regulate social behavior including hippocampus, hypothalamus, and rhinal cortex. Alongside perfusion deficits at 60dpi, social isolation in TBI-mice emerged with a significant decline in preference to spend time with a cage mate. Cortical vascular density was also reduced corroborating the decline in brain perfusion and social interaction.
Thus, the novel temporal neurovascular loss, and subsequent recovery followed by chronic decrements are broadly reflected by social interaction perturbations. Our correlations strongly implicate a linkage between vascular density, cerebral perfusion, and social interactions, where early evaluation can potentially predict long-term outcomes. Thus, our study provides a clinically relevant timeline of alterations in functional vascular recovery that can guide research for future therapeutics.
... Social interactions are impaired after TBI with reductions in interpersonal communication, 9 time with friends and families, 10,11 and is evident in children 12,13 and adults. 14,15 Social behavior is also diminished in adult mice after a single 16,17 or repeated-mild TBI, 18,19 and in pediatric models of TBI. 20 Social isolation in rodents reflects increased neuropathology after TBI, 21 however, increased social interaction post-injury is known to facilitate recovery. ...
Traumatic brain injury (TBI) survivors face debilitating long-term psychosocial consequences, including social isolation and depression. Acute TBI modifies neurovascular physiology and behavior but a gap in our understanding are the chronic physiological implications of altered brain perfusion on behavioral activities, particularly social interactions. We investigated longitudinal functional vascular networks across the brain for 2-months post-TBI and its impact on social behavior. Adult C57/BL6 male mice received a moderate cortical TBI. Behavior (foot-fault, open-field, 3-chamber social preference) was assessed at baseline, 3-, 7-, 14-, 30-, and 60-days post injury (dpi) followed by magnetic resonance imaging (MRI, 9.4T). Anatomical MRI (T2-weighted), dynamic susceptibility contrast (DSC) perfusion weighted MRI (PWI) were acquired at each temporal epoch. After the final 60dpi MRI, animals underwent transcardial perfusion fixation to map angioarchitecture. MRI data were analyzed using standardized protocols followed by cross-correlations between social behavior, cerebral perfusion, and vascular metrics. Social behavior deficits at 60dpi emerged as reduced interaction with a familiar cage-mate (partner). We observed multiphasic decrements in cerebral blood flow (CBF) encompassing lesion and perilesional cortex where acute reductions at 3-14dpi partially recovered by 30dpi, followed by significant reductions in perfusion at 60dpi. The CBF perturbations extended antero-posteriorly from the ipsilateral TBI impact site but also adulterated contralateral brain regions. CBF reductions impacted regions known to regulate social behavior including hippocampus, hypothalamus, and rhinal cortex. Alongside perfusion deficits at 60dpi, social isolation in TBI-mice emerged with a significant decline in preference to spend time with a cage mate. Cortical vascular density was also reduced corroborating the decline in brain perfusion and social interaction. Thus, the novel temporal neurovascular loss, and subsequent recovery followed by chronic decrements are broadly reflected by social interaction perturbations. Our correlations strongly implicate a linkage between vascular density, cerebral perfusion, and social interactions, where early evaluation can potentially predict long-term outcomes. Thus, our study provides a clinically relevant timeline of alterations in functional vascular recovery that can guide research for future therapeutics.
... Recently we reported that moderate-to-severe TBI caused alterations in the bone marrow compartment that subsequently led to leukopenia and reduction in white blood cell production in the femur (24,40). To begin our next series of investigations into the brain-bone marrow axis, we examined the effect of TBI on stress-induced myelopoiesis. ...
... Acute stress-induce myelopoiesis was accompanied by neutrophilia and peripheral immune suppression during the early phase. Deficits in phagocytosis and elevated oxidative stress levels persisted for months after injury, associated with the development of leukopenia and bone marrow failure at one-year post-injury (24,44). Importantly, we found that bone marrow-derived macrophage cultures harvested from chronic (90d) TBI mice exhibited significantly higher sensitivity to LPS stimulation compared to macrophages cultured from sham mice (45,46). ...
... The chronic phase of moderate-to-severe TBI is highlighted by neurological decline, including motor disability and cognitive worsening (60,61). We and others have previously reported long-term neurological deficits in mice using the CCI model (24,25,27,62). In this study, we showed that TBI inherently altered bone marrow cells which could independently drive neurological dysfunction in the absence of primary brain injury. ...
Traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function which contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham congenic donor mice into otherwise healthy, age-matched, irradiated hosts. After 8 weeks of reconstitution, peripheral myeloid cells from TBIàWT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBIàWT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI showed that longer reconstitution periods were associated with increased microgliosis and leukocyte infiltration. Thus, TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in innate immunity and neurological function, as well as altered sensitivity to subsequent brain injury.
... Recently we reported that moderate-to-severe TBI caused alterations in the bone marrow compartment that subsequently led to leukopenia and reduction in white blood cell production in the femur (24,40). To begin our next series of investigations into the brain-bone marrow axis, we examined the effect of TBI on stress-induced myelopoiesis. ...
... Acute stress-induce myelopoiesis was accompanied by neutrophilia and peripheral immune suppression during the early phase. Deficits in phagocytosis and elevated oxidative stress levels persisted for months after injury, associated with the development of leukopenia and bone marrow failure at one-year post-injury (24,44). Importantly, we found that bone marrow-derived macrophage cultures harvested from chronic (90d) TBI mice exhibited significantly higher sensitivity to LPS stimulation compared to macrophages cultured from sham mice (45,46). ...
... The chronic phase of moderate-to-severe TBI is highlighted by neurological decline, including motor disability and cognitive worsening (60,61). We and others have previously reported long-term neurological deficits in mice using the CCI model (24,25,27,62). In this study, we showed that TBI inherently altered bone marrow cells which could independently drive neurological dysfunction in the absence of primary brain injury. ...
Traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function which contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham congenic donor mice into otherwise healthy, age-matched, irradiated hosts. After 8 weeks of reconstitution, peripheral myeloid cells from TBIàWT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBIàWT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI showed that longer reconstitution periods were associated with increased microgliosis and leukocyte infiltration. Thus, TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in innate immunity and neurological function, as well as altered sensitivity to subsequent brain injury.
... Indeed, our lab and others have experimentally shown that peripheral infections during acute and chronic stages of TBI are more severe compared to sham controls and often cause bidirectional damage 17,18,19,20,21,22 . Although we have demonstrated that chronic microglial activation can aggravate posttraumatic neurodegeneration 23,24,25,26 , the long-term consequences and progression of bone marrow dysfunction following brain injury remains largely undocumented. ...
... Recently we reported that moderate-to-severe TBI caused alterations in the bone marrow compartment that subsequently led to leukopenia and reduction in white blood cell production in the femur 24,40 . To begin our next series of investigations into the brain-bone marrow axis, we examined the effect of TBI on stress-induced myelopoiesis. ...
... Acute stress-induce myelopoiesis was accompanied by neutrophilia and peripheral immune suppression during the early phase. Deficits in phagocytosis and elevated oxidative stress levels persisted for months after injury, associated with the development of leukopenia and bone marrow failure at one-year post-injury 24,44 . Importantly, we found that bone marrow-derived macrophage cultures harvested from chronic (90d) TBI mice exhibited significantly higher sensitivity to LPS stimulation compared to macrophages cultured from sham mice 45,46 . ...
Traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function which contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined. To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham congenic donor mice into otherwise healthy, age-matched, irradiated hosts. After 8 weeks of reconstitution, peripheral myeloid cells from TBI→WT mice showed significantly higher oxidative stress levels and reduced phagocytic activity. At eight months after reconstitution, TBI→WT chimeric mice were leukopenic, with continued alterations in phagocytosis and oxidative stress responses, as well as persistent neurological deficits. Gene expression analysis revealed BM-driven changes in neuroinflammation and neuropathology after 8 weeks and 8 months of reconstitution, respectively. Chimeric mice subjected to TBI showed that longer reconstitution periods were associated with increased microgliosis and leukocyte infiltration. Thus, TBI causes chronic activation and progressive dysfunction of the BM stem/progenitor cell pool, which drives long-term deficits in innate immunity and neurological function, as well as altered sensitivity to subsequent brain injury.
... Generally, neurological impairment after TBI was caused by its pathological changes, such as neuronal damage and synaptic plasticity dysfunction (Hernandez et al., 2018;Chen et al., 2020;McDaid et al., 2021;Wang et al., 2022). It was reported that neuronal cell death was observed in TBI mice (Xie et al., 2019), and the levels of synaptophysin and PSD-95 were reduced in TBI mice (Ritzel et al., 2020;Zhuang et al., 2023). Xiao et al. proved that FMT enhanced neuronal survival in the hippocampus in rats with chronic cerebral hypoperfusion . ...
Introduction
Recent studies have highlighted the vital role of gut microbiota in traumatic brain injury (TBI). Fecal microbiota transplantation (FMT) is an effective means of regulating the microbiota–gut–brain axis, while the beneficial effect and potential mechanisms of FMT against TBI remain unclear. Here, we elucidated the anti-neuroinflammatory effect and possible mechanism of FMT against TBI in mice via regulating the microbiota–gut–brain axis.
Methods
The TBI mouse model was established by heavy object falling impact and then treated with FMT. The neurological deficits, neuropathological change, synaptic damage, microglia activation, and neuroinflammatory cytokine production were assessed, and the intestinal pathological change and gut microbiota composition were also evaluated. Moreover, the population of Treg cells in the spleen was measured.
Results
Our results showed that FMT treatment significantly alleviated neurological deficits and neuropathological changes and improved synaptic damage by increasing the levels of the synaptic plasticity-related protein such as postsynaptic density protein 95 (PSD-95) and synapsin I in the TBI mice model. Moreover, FMT could inhibit the activation of microglia and reduce the production of the inflammatory cytokine TNF-α, alleviating the inflammatory response of TBI mice. Meanwhile, FMT treatment could attenuate intestinal histopathologic changes and gut microbiota dysbiosis and increase the Treg cell population in TBI mice.
Conclusion
These findings elucidated that FMT treatment effectively suppressed the TBI-induced neuroinflammation via regulating the gut microbiota–gut–brain axis, and its mechanism was involved in the regulation of peripheral immune cells, which implied a novel strategy against TBI.
... In this scenario, microglia seem to be the main player in TBI-associated neuroinflammation through release of numerous inflammatory mediators, driving progressive lesion expansion, loss of myelin, neurodegeneration, and cognitive disfunction [111,112]; microglial deletion, 1 month after TBI, to remove chronically reactive hypertrophic microglia and subsequent repopulation by ramified microglia, resulted in reduced neuroinflammation, neurodegeneration, and improved cognition in rats [113]. In this scenario, exercise exerts important roles following TBI by modulating microglial reactivity [78] and neuroinflammatory status, which is a determinant for neurological outcomes and ultimately the quality of life. ...
Physical exercise is well known as a non-pharmacological and holistic therapy believed to prevent and mitigate numerous neurological conditions and alleviate ageing-related cognitive decline. To do so, exercise affects the central nervous system (CNS) at different levels. It changes brain physiology and structure, promoting cognitive improvements, which ultimately improves quality of life. Most of these effects are mediated by neurotrophins release, enhanced adult hippocampal neurogenesis, attenuation of neuroinflammation, modulation of cerebral blood flow, and structural reorganisation, besides to promote social interaction with beneficial cognitive outcomes. In this review, we discuss, based on experimental and human research, how exercise impacts the brain structure and function and how these changes contribute to cognitive improvements. Understanding the mechanisms by which exercise affects the brain is essential to understand the brain plasticity following exercise, guiding therapeutic approaches to improve the quality of life, especially in obesity, ageing, neurodegenerative disorders, and following traumatic brain injury.
